Fueling brain function in an extreme model of metabolic plasticity

The National Science Foundation's Division of Emerging Frontiers awarded the University of Missouri System $914,424 under the Biological Sciences (CFDA 47.074) program for the project "Fueling Brain Function in an Extreme Model of Metabolic Plasticity." The award, obligated on September 15, 2025, with completion targeted for August 31, 2028, supports fundamental research investigating how bullfrog brains sustain neural function during hibernation without glucose and oxygen—a capability that far exceeds documented metabolic plasticity in other vertebrate species. The research tests the hypothesis that ketone bodies derived from fat metabolism can exclusively fuel brain activity under severe metabolic stress conditions. By elucidating the neurobiological mechanisms underlying this extreme metabolic adaptation, the project aims to generate scientific knowledge applicable to understanding and potentially improving brain function in neurodegenerative diseases of metabolic origin, including Alzheimer's disease, Parkinson's disease, and ALS (amyotrophic lateral sclerosis).

The project includes a sub-award to the San Diego Zoo Wildlife Alliance, dated September 10, 2025, supporting collaborative research services essential to the investigation. Beyond its primary research outputs—novel data on ketone metabolism in neural tissue, methodological advances, and peer-reviewed publications—the grant supports workforce development through graduate student training and the establishment of an educational pipeline incorporating international relations at the University of Missouri. This training component aligns with the Biological Sciences program's emphasis on strengthening the nation's scientific enterprise through enhanced human capital development in the biological sciences.

Abstract

Brain function has high energy demands, and when these needs are not met there is a loss of neural function. Most of the energy for brain function comes from burning sugar (GLUCOSE) using oxygen. In contrast, preliminary observations led to discovery of an alternate scenario whereby bullfrogs display an unusually large ability to abandon these conventional energy sources to promote survival. Like most vertebrates, brain activity in frogs typically requires energy from GLUCOSE metabolism. However, hibernation transforms the bullfrog brain to function for over two hours without GLUCOSE and oxygen, promoting survival when these resources are otherwise limited. This represents the largest improvement in neural activity during severe metabolic stress reported in the vertebrate brain. This project tests the hypothesis that this impressive feat involves the metabolism of by-products of FAT breakdown (ketone bodies) without any ongoing GLUCOSE metabolism. While ketone bodies are well-known to fuel the brain during starvation and certain diets, neural function in most animals requires at least some GLUCOSE at the same time. As issues with GLUCOSE metabolism contribute to diverse neurological disorders, including alzheimer?S disease, parkinson?S disease, and ALS, these studies have long-term implications for improving brain function in neurodegenerative diseases of metabolic origin. This project will also train graduate students, including introducing a pipeline for education training that incorporates international relations at the university of missouri. During winter hibernation, bullfrogs adapt to conditions in which they experience low metabolic rates, starvation, and low oxygen and GLUCOSE blood levels. Emergence from these conditions in the spring requires neural circuits to become active in conditions that are atypical for vertebrates. Previously, these investigators found that neurons in respiratory brainstem circuits can shift to alternative fuel sources during hibernation. This project they will test the hypothesis that frogs switch from GLUCOSE to ketone metabolism. Circuit physiology approaches will be used to test that switching to ketones and other non-GLUCOSE fuels improves activity during hypoxia, in part through upregulation of ketone body transporters. Combining single-cell electrophysiology and RNA-sequencing, the researchers will then test the hypothesis that synaptic physiology and metabolism are preferentially modified to allow the exclusive use of non-GLUCOSE fuels. Finally, biochemical approaches and cutting-edge methods will be used to measure mitochondrial function and test the hypothesis that neurophysiological adjustments are matched at the mitochondria to maintain ATP homeostasis when running only on non-GLUCOSE fuels. Overall, this project will uncover plasticity that improves the brain?S capacity to run on alternative energy sources. The results are expected to reveal how an animal reconfigures the brain to function without GLUCOSE metabolism and to put forth a framework that guides strategies to boost the use of non-GLUCOSE energy sources. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the foundation's intellectual merit and broader impacts review criteria.- subawards are planned for this award.